Application of transition metal catalysts in organic synthesis

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Preface

The present book may be considered as a continuation of our laboratory manuals dealing with the chemistry of acetylenes, allenes and polar organometallics It con-tains a number of experimental procedures for the catalytic use of copper, nickel and palladium compounds in organic synthesis based on methods described in literature and carried out by the authors of this book and their coworkers The original plan was to cover a much broader field of transition metal chemistry, but this was soon dropped as being too ambitious It would take too much time and effort to become familiar with all experimental methods in the extensive field of transition metal-cat-alyzed organic synthesis, a necessary condition to develop reliable procedures We therefore decided to restrict ourselves to sub-fields in which some experience had been acquired in our laboratory The various methods are exemplified with proce-dures on a preparative scale, usually 50 or 100 mmolar, using normal laboratory glassware and reagents and starting compounds which are either relatively cheap or readily preparable In addition, literature surveys of the various subjects are given

We are indebted to Diosynth, DSM and Shell for additional financial and material support

Table of Contents

1 Catalysts, Ligands and Reagents

1.1 Catalysts

1.1.1 Copper Halides

1.1.1.1 Solubilization of Copper(I) Halides

1.1.2 Nickel Catalysts _~ 2

1.1.2.1 Nickel(II)bromide·bis( triphenylphosphane) 2

1.1.2.2 Nickel(II)chloride·bis(triphenylphosphane) 2

1.1.2.3 Nickel(II)chloride·l,3-bis( diphenylphosphino) propane 2

1.1.2.4 Nickel(II)chloride·l,2-bis( diphenylphosphino )ethane 2

1.1.2.5 Nickel(II)chloride·l,4-bis( diphenylphosphino )butane 2

1.1.2.6 Nickel(II)chloride·l,1 '-bis( diphenylphosphino) ferrocene 3

1.1.2.7 Nickel(II)bromide·l,l' -bis( diphenylphosphino) ferrocene 3

1.1.2.8 trans-Chloro( 1-naphthyl) bis( triphenylphosphane) nickel 3

1.1.2.9 trans-Bromo( I-naphthyl)bis( triphenylphosphane) nickel and trans-Bromo(phenyl)bis (triphenyl-phosphane)nickel 4

1.1.3 Palladium Catalysts , 4

1.1.3.1 Palladiurn(II)chloride·bis(acetonitrile) 4

1.1.3.2 Palladium(II)chloride·bis(benzonitrile) 4

1.1.3.3 Palladiurn(II)chloride·bis( triphenylphosphane) 4

1.1.3.4 Palladium(II)chloride·l,4-bis( diphenylphosphino) butane ' 4

1.1.3.5 Palladium(II)chloride·l,l' -bis( diphenylphosphino) ferrocene 5

1.1.3.6 Tetrakis(triphenylphosphane)palladium(O) 5

1.1.3.7 Tris(dibenzylideneacetone)dipalladium(O)·chloroform 6

1.2 Ligands 6

1.2.1 l,n-Bis(diphenylphosphino)alkanes (n= 2,3,4) 6

1.2.1.1 1,2-Bis( diphenylphosphino )ethane 7

1.2.1.2 1,3-Bis(diphenylphosphino)propane 7

1.2.1.3 1,4-Bis( diphenylphosphino )butane 8

1.2.2 1,l'-Bis(diphenylphosphino)ferrocene 8

1.2.3 Triarylphosphanes and Tri(hetaryl)phosphanes 9

1.3 Organometallic Reagents 10

1.3.1 Preparation of Grignard Reagents from Mg and Organic Halides 10

1.3.2 Preparation of Organomagnesium and Organozinc Halides by Lithium-Magnesium or Lithium-Zinc Exchange 12

1.3.3 Preparation of Organoaluminum Intermediates 13

1.3.4 Preparation of Organoboron and Organotin Intermediates 13

1.3.4.1 2-Thiopheneboronic Acid 13

1.3.4.2 2-Furanboronic Acid 14

1.3.4.3 4-(Fluorophenyl)boronic Acid 14

1.3.4.4 (2-Methoxyphenyl)boronic Acid 15

1.3.4.5 2-Tributylstannylfuran 15

1.3.4.6 1-Methyl-2-tributylstannylpyrrole 15

1.3.4.7 4-Methyl-2-tributylstannylthiazole 16

1.3.4.8 Stannylation of Ethyl Vinyl Ether 17

2 Procedures for the Preparation of Halogen Compounds 19

2.1 sp-Halides 19

2.1.1 1-Bromo-1-propyne and 1-Bromo-1-butyne 19

2.1.2 1-Bromo-1-pentyne and 1-Bromo-1-hexyne 20

2.1.3 Other 1-Bromo-1-alkynes 21

2.1.4 Reaction of Alkynyllithium with Iodine in Organic Solvents 22

2.1.5 Preparation ofIodoacetylenes from Lithiated Acetylenes and Iodine in Liquid Ammonia 22

2.2 Aryl and Hetaryl Halides 24

2.2.1 2-Bromothiophene 24

2.2.2 2,5-Dibromothiophene 25

2.2.3 2,3,5-Tribromothiophene 25

2.2.4 3-Bromothiophene 26

2.2.5 2,3-Dibromothiophene 26

2.2.6 3,4-Dibromothiophene 27

2.2.7 2,4-Dibromothiophene 28

2.2.8 2-Bromofuran 29

2.2.9 2,3-Dibromofuran 30

2.2.10 3-Bromofuran 31

2.2.11 2,5-Dibromofuran 31

2.2.12 2-Iodothiophene 32

2.2.13 3-Iodothiophene 33

2.2.14 2-Iodofuran 33

2.2.15 2-Iodo-1-methylimidazole 34

Table of Contents IX

2.2.16 2-Iodo-l-methylpyrrole 34

2.2.17 I-Bromo-4-iodobenzene 35

2.2.18 3-Bromoquinoline 36

2.3 Olefinic, Cycloolefinic and Allenic Halides 36

2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.3.8 2.3.9 2.3.10 2.3.11 2.3.12 2.3.13 2.3.14 2.3.15 I-Bromo-2-methylpropene 36

a-Bromostyrene 37

2-Bromo-l-ethoxyethene 38

3-Bromo-5,6-dihydro-4H-pyran 38

I-Bromocyclooctene 39

l-Chlorocyclohexene 40

Z-I,4-Dibromo-2-butene and I-Bromo-l,3-butadiene 40

E-l,4-Dibromo-2-butene and I-Bromo-l,3-butadiene 42

2-Bromo-l,3-butadiene 42

I-Bromo-3-methyl-1,2-butadiene .• 43

I-Bromo-1,2-butadiene 44

1-Bromocyclohexene 44

1-Bromocyclopentene 45

E-l-Bromo-1-octene 46

E-1-Iodo-1-heptene 47

3 Cross-Coupling Between l-Alkynes and I-Bromoalkynes 49

3.1 Introduction 49

Table 1 50

3.2 Scope and Limitations 53

3.3 Relative Reactivities of the Acetylene and the Bromoacetylene 53

Table 2 54

3.4 Conditions for the Coupling 56

3.5 Choice of the Reaction Partners 57

3.6 Side Reactions 57

3.7 Experimental Part 58

3.7.1 General Remarks and Some Observations 58

3.7.2 Performance of Cu-Catalyzed Cadiot-Chodkiewicz Couplings 59

3.7.3 Typical Procedure for the Pd/Cu-Catalyzed Cross Coupling Between 1-Bromo-1-alkynes and Acetylenes 60

4 Copper-Catalyzed Aminoalkylation of Acetylenes 61

4.1 Introduction, Scope and Mechanism 61

4.2 Experimental Part 63

4.2.1 Reaction of Acetylenic Alcohols with Dimethylaminomethanol 63

4.2.2 General Procedure for the Mannich Reaction of Acetylenes Without an OH-Function 64

4.2.3 Mannich Reactions with Gaseous Acetylenes 66

5 Copper(I)-Halide-Catalyzed Oxidative Coupling of Acetylenes 67

5.1 Introduction 67

5.2 Methods, Scope and Limitations 67

5.3 About the Mechanism 69

5.4 Experimental Part 71

5.4.1 Oxidative Coupling of Prop argyl Alcohol Catalyzed by Copper(I)Chloride in Aqueous Medium 71

5.4.2 Oxidative Couplings Catalyzed by Copper(I)Chloride·TMEDA in Acetone 72

5.4.2.1 Oxidative Coupling of Methyl Propargyl Ether 72

5.4.2.2 Oxidative Coupling of 3-Butyn-2-o1 73

5.4.2.3 Oxidative Coupling of2-Methyl-3-butyn-2-o1 73

5.4.2.4 Oxidative Coupling of 3-Butyn-1-o1 74

5.4.2.5 Oxidative Coupling of 1-Methoxy-1-buten-3-yne 74

5.4.2.6 Oxidative Coupling of Arylacetylenes 75

5.4.2.7 Oxidative Coupling of Prop argyl Alcohol 75

5.4.3 Oxidative Couplings Catalyzed by Copper(I)Chloride·TMEDA in N,N-Dimethylformamide 76

5.4.3.1 Oxidative Coupling of 1,1-Diethoxy-2-propyne 76

5.4.3.2 Oxidative Coupling of Ethyl Prop argyl Sulfide 76

5.4.4 Oxidative Couplings Catalyzed by Copper(I)Chloride in Pyridine 77

5.4.4.1 Oxidative Coupling of 4-Butyn-1-o1 77

5.4.4.2 Oxidative Coupling of2-Ethynylpyridine 78

5.4.5 Oxidative Couplings Catalyzed by Copper(I)Chloride and Diazabicydoundecene 78

5.4.5.1 Oxidative Coupling of 1-Butyne 78

5.4.5.2 Oxidative Coupling of2-Ethynyl-1-methylpyrrole 79

5.4.5.3 Oxidative Coupling of t -Butylacetylene 79

5.4.6 Oxidative Coupling of Trimethylsilylacetylene 80

5.4.7 Oxidative Coupling of the HCI-Salt of 3-Amino-3-methyl-1-butyne 80

Table of Contents XI

5.5 Summary of Experimental Conditions for Oxidative Couplings 81

Table 3 82

6 Copper(I)-Halide-Catalyzed Substitution of sp2-Halogen by Alkoxide 85

6.1 Introduction 85

6.2 Scope and Limitations of the Copper-Catalyzed Nucleophilic Substitution of Sp2_ Halogen by Alkoxy Groups 86

Table 4 87

6.3 Mechanistic Investigations 93

6.4 Reaction Conditions 93

6.4.1 Solvent and Reaction Temperature 93

6.4.2 The Catalyst 94

6.5 Differences in the Reactivities of the Various sp2_ Halides 95

6.6 Side Reactions 96

6.7 Applications 97

6.8 Experimental Part 97

6.8.1 General 97

6.8.1.1 Reaction Conditions and Observations 97

6.8.1.2 Apparatus and Equipment 98

6.8.2 Methoxylation 99

6.8.2.1 2-Methoxythiophene 99

6.8.2.2 3-Methoxythiophene 100

6.8.2.3 3-Methoxypyridine 100

6.8.2.4 3,4-Dimethoxythiophene 101

6.8.2.5 I-Methoxycyclooctene 101

6.8.3 Other Alkoxylations 102

6.8.3.1 2-Ethoxythiophene 102

6.8.3.2 3-Ethoxythiophene 102

6.8.3.3 3-Isopropoxythiophene 102

6.8.3.4 2-(2'Dimethylaminoethoxy)furan 102

6.8.3.5 2-(2'Dimethylaminoethoxy)thiophene 103

6.8.3.6 1-(2'Dimethylaminoethoxy)cyclooctene 103

6.8.3.7 2-(2'Methoxyethoxy)thiophene 103

6.8.3.8 1,4-Bis(2,2,2-trifluoroethoxy)benzene 104

7 Copper-Catalyzed Carbon-Carbon Bond Formation

by 1,1- and 1,3-Substitution Reactions 107

7.1 Introduction 107

7.2 Displacement of Halide, Tosylate and Acetate in Saturated Compounds 108

7.3 Ring Opening of Saturated Epoxides 109

7.4 Reactions with Allylic Substrates 110

7.5 Reactions with Propargylic and Allenic Substrates 114

7.6 About the Mechanism of Copper Catalyzed Substitutions 116

7.7 Experimental Section 118

7.7.1 Alkylation Reactions with Halides and Tosylates 118

7.7.1.1 2,2,7,7-Tetramethyloctane 118

7.7.1.2 5,5-Dimethylhexan-l-ol 119

7.7.1.3 Selective Substitution of Bromine in I-Bromo-4-chlorobutane 120

7.7.1.4 Selective Mono-Substitutions with l,n-Dibromoalkanes 120

7.7.1.5 Displacement of Tosylate in Alkyl Tosylates 121

7.7.1.6 Neopentylbenzene 122

7.7.1.7 Benzyl-Aryl Couplings 122

7.7.1.8 t-Butylallene 123

7.7.1.9 Coupling Between Prop argyl Alcohol and Prop argyl Chloride in Aqueous Solution 124

7.7.1.10 Couplings Between Acetylenic Grignard Reagents and AllylBromide or Propargyl Bromide 124

7.7.1.11 Reactions of Grignard Reagents with Propargylic Tosylates 125

7.7.2 Substitutions with Cyclic and Non-Cyclic Ethers 126

7.7.2.1 Preparation of l-Alkenyl Ethers from Grignard Reagents and 1,I-Diethoxy-2-propene 126

7.7.2.2 Reaction of Phenylmagnesium Bromide with Cyclo-hexene Oxide 127

7.7.2.3 Preparation of Allenic Ethers from Propargylaldehyde Diethylacetal and Grignard Reagents 127

7.7.2.4 Cyclohexylallene 128

7.7.2.5 Preparation of Allenic Alcohols from Acetylenic Epoxides and Grignard Reagents 128

7.7.2.6 Reaction of2-Ethynyhetrahydropyran with a Grignard Reagent 129

7.7.2.7 3-Cyclopentyl-l-propyne 129

Table of Contents XIII

8 Nickel Catalyzed Iodo-Dechlorination and

Iodo-Debromination of sp2-Halides 141

8.1 Introduction 141

8.2 Scope and Limitations 141

8.3 Mechanistic Investigations 143

8.4 Side Reactions , 143

8.5 Experimental Procedures 145

8.5.1 Conversion of 1-Bromocyclooctene into 1-Iodocyclooctene 145

8.5.2 1-Iodocyclohexene from 1-Chlorocyclohexene (Zn/NiBr2) 146

8.5.3 1-Iodocyclohexene from 1-Chlorocyclohexene (Ni(CODh) 147

8.6 Conclusions from our Investigations 147

9 Nickel- and Palladium-Catalyzed Cyanation of Sp2_ Halides and Sp2_ Tritlates 149

9.1 Introduction 149

9.2 Scope and Limitations 149

Table 7 151

9.3 Mechanism of the Nickel Catalyzed Cyanation 163

9.4 Methods of Performing Nickel Catalyzed Cyanations 166

9.5 Relative Reactivities of sp2-Halides 168

9.6 Side Reactions 168

9.7 Catalysis by Palladium Compounds 169

9.8 Experimental Part 170

9.8.1 General Procedure for the Nickel Catalyzed Cyanation of sp2-Halides in Absolute Ethanol 171

9.8.2 General Procedures for Cyanations Proceeding Under the

Influence of a NiO-Catalyst Generated by Reducing a Ni

II-Precatalyst with Zinc Powder 174

9.8.2.1 Cyanation of p-Chlorobenzotrifluoride 175

9.8.2.2 Cyanation of 1-Bromocyclooctene 176

9.8.3 Palladium-Catalyzed Cyanation of Aryl Iodides 176

9.8.4 Palladium-Catalyzed Cyano-Debromination of Bromoolefins 177

10 Couplings of Acetylenes with Sp2_ Halides 179

10.1 Introduction 179

10.2 Mechanistic Considerations 180

10.3 Scope and Limitations 181

Table 8 183

10.4 Relative Rates of Coupling 191

10.5 Regiochemistry and Stereochemistry 191

10.6 Synthetic Applications of the Cross-Coupling Reactions with Acetylenes 193

10.6.1 Simple Applications of the Cross-Coupling 193

10.6.2 Synthesis of Structurally Interesting Acetylenic Compounds 194

10.6.3 Coupling Followed by Cyclization 195

10.6.4 Synthesis of Biologically Interesting Compounds 196

10.6.5 Special Methods 197

10.7 Practical Aspects of the Coupling Reactions 198

10.7.1 Performance of the Reactions and Isolation of the Products 198

10.7.2 Choice of the Solvent and Catalysts for Coupling Reactions 200

10.8 Experimental Section 201

10.8.1 Pd/Cu-Catalyzed Cross Couplings of Acetylenic Compounds with Aliphatic sp2-Halides Using Diethylamine as a Solvent 201

10.8.1.1 4-Penten-2-yn-1-o1 201

10.8.1.2 4-Methyl-4-penten-2-yn-1-ol 202

10.8.1.3 1-Nonen-3-yne 203

10.8.1.4 2-Methyl-6-trimethylsilylhexa -2,3-dien -5-yne 203

10.8.1.5 6-Ethoxy-2-methylhex-5-en-3-yn-2-ol 203

10.8.1.6 6-Ethoxyhex-5-en-3-yn-2-ol 204

10.8.1.7 2,5-Dimethylhex-5-en-3-yn-2-ol 204

10.8.1.8 2,6-Dimethylhep-5-en-3-yn-2-ol 204

Table of Contents xv

10.8.1.9 5-Trimethylsilylethynyl-2,3-dihydro-4H-pyran 204

10.8.1.10 6-Chloro-2-methylhex-5-en-3-yn-2-ol 205

10.8.1.11 1-Chlorodec-1-en-3-yne 205

10.8.1.12 2-Chlorooct-1-en-3-yne 206

10.8.1.13 Other Cross Couplings, Using Similar Conditions 206

10.8.2 Pd/Cu-Catalyzed Couplings of Acetylene with Aryl and Hetaryl Halides 206

10.8.2.1 1,2-Bis( 4-acetylphenyl)ethyne 206

10.8.2.2 Bis(4-methylphenyl)ethyne 207

10.8.2.3 Di(2-pyridyl)ethyne 207

10.8.2.4 Di(2-thienyl)ethyne 207

10.8.2.5 Di(3-thienyl)ethyne 208

10.8.2.6 Bis(1-methylimidazol-2-yl)ethyne 208

10.8.3 Pd/Cu-Catalyzed Couplings of Acetylenic Compounds with Aryl and Hetaryl Halides Using Diethylamine as a Solvent 208

10.8.3.1 1-Nitro-4-( trimethylsilylethynyl) benzene 208

10.8.3.2 3-Bromo-4-trimethylsilylethynylthiophene 209

10.8.3.3 2-(Penta-1,3-diynyl)thiophene 209

10.8.4 Pd/Cu-Catalyzed Couplings of Acetylenic Compounds with Aryl and Hetaryl Halide Using Triethylamine as a Solvent 210

10.8.4.1 2-(Trimethylsilylethynyl)thiophene 210

10.8.4.2 2-(Trimethylsilylethynyl)furan 211

10.8.4.3 3-(Trimethylsilylethynyl)pyridine 211

10.8.4.4 3-(4-Nitrophenyl)prop-2-yn-1-01 211

10.8.4.5 4-(Trimethylsilylethynyl)acetophenone 211

10.8.4.6 2-Methyl-4-(4-methoxyphenyl)but-3-yn-2-01 212

10.8.4.7 3-(2-Thienyl)prop-2-yn-1-01 212

10.8.4.8 2-Methy14-(2-methoxyphenyl)but-3-yn-2-01 212

10.8.4.9 4,4' -(Thiophene-2,5-diyl)di -(2-methylbut -3-yn -2-0l) 213

10.8.4.10 1-Methyl-2(trimethylsilylethynyl)pyrrole 213

10.8.4.11 4- (4-Dimethylaminophenyl)-2-methylbut -3-yn -2-01 213

10.8.5 Pd/Cu-Catalyzed Couplings of Acetylenic Compounds Using Diisopropylamine as a Solvent 214

10.8.5.1 1,3-Bis( trimethylsilylethynyl) benzene 214

10.8.5.2 3-(Cyclooct-1-enyl)prop-2-yn-1-01 214

10.8.5.3 1-Trifluoromethyl, 2-( trimethylsilylethynyl) benzene 215

10.8.5.4 3-(4-Fluorophenyl)-N,N-dimethylprop-2-yn-1-amine 215

10.8.5.5 1-{3-(l-Ethoxyethoxy)prop-1-ynyl}-4-fluorobenzene 215

10.8.5.6 1-Methoxy-4-(trimethylsilylethynyl)benzene 216

10.8.5.7 4-(3-Furyl)-2-methylbut-3-yn-2-01 216

10.8.6 Pd/Cu-Catalyzed Couplings with Acetylenic Compounds, Using Piperidine as a Solvent 216

10.8.6.1 1-Ethynylcyclooctene 216

10.8.6.2 2-Chloro-l-ethynylbenzene 217

10.8.6.3 4-Fluoro-1-( trimethylsilylethynyl)benzene 217

10.8.6.4 3-(Trimethylsilylethynyl)thiophene 218

10.8.6.5 1-Methoxy-4-( trimethylsilylethynyl)benzene 218

10.8.6.6 4-N ,N -Dimethylamino-1-ethynylbenzene 218

10.8.6.7 5-(Trimethylsilylethynyl)-2,3-dihydro-4H -pyran 219

10.8.7 Preparation of2-Ethynylarenes and -hetarenes by Pd/Cu-Catalyzed Cross Coupling of Bromoarenes or -hetarenes with 2-Methyl-3-butyn-2-ol and Subsequent KOH-Catalyzed Elimination of Acetone 219

10.8.7.1 4-(2-Thienyl)-2-methylbut-3-yn-2-ol and 2-Ethynylthiophene 219

10.8.7.2 4-(4-Fluorophenyl)-2-methylbut-3-yn-2-ol and 1-Ethynyl-4-fluorobenzene 220

10.8.7.3 4-( 4-Chlorophenyl)-2-methylbut -3-yn-2-01 and 4-Chloro-1-ethynylbenzene 220

10.8.7.4 4-(2-Furyl)-2-methylbut-3-yn-2-ol and 2-Ethynylfuran 221

10.8.8 Pd/Cu-Catalyzed Mono-Substitutions with Aryl or Hetaryl Dibromides 222

10.8.8.1 4-(3-Bromothienyl)-2-methylbut-3-yn-2-ol 222

10.8.8.2 3-Bromo-2-(trimethylsilylethynyl)furan 223

10.8.8.3 3-Bromo-2-(trimethylsilylethynyl)thiophene 223

10.8.8.4 4-(2-Bromophenyl)-2-methylbut-3-yn-2-ol 223

10.8.9 Preparation of Disubstituted Acetylenes by Pd/Cu-Catalyzed Reactions with Aryl and Hetaryl Iodides in the Presence of an Amine and Sodium Methoxide 224

10.8.9.1 4-(4-Bromophenyl)-2-methylbut-3-yn-2-ol 224

10.8.9.2 1-(4-Methoxyphenyl)-2-phenylethyne 225

10.8.9.3 3-(Phenylethynyl)thiophene 225

11 Nickel- and Palladium-Catalyzed Cross-Coupling Reactions with Organometallic Intermediates 227

11.1 Introduction 227

11.2 Possibilities of Connecting Organic Groups by Transition Metal Catalysis , 228

11.3 Catalysts and Ligands 228

11.4 Leaving Groups 231

11.5 Couplings with Organolithium Compounds 235

11.6 Couplings with Organomagnesium and Organozinc Halides 237

11.7 Cross Couplings with Organoaluminum, Organoboron and Organotin Compounds 238

Table of Contents XVII

11.8 Regiochemical and Stereochemical Aspects 239

11.9 Mechanism and Side Reactions 242

11.10 Practical Aspects of Transition-Metal-Catalyzed Couplings 244

11.11 Experimental Section 247

11.11.1 Nickel-Catalyzed Cross-Couplings with Alkylmagnesium Halides 248

11.11.1.1 3-n-Octylthiophene 248

11.11.1.2 3-Cyclohexylthiophene 248

11.11.1.3 3-Benzylthiophene 249

11.11.1.4 {2,2-Dichlorovinyl)cyclohexane 249

11.11.1.5 2-Cyclohexylbenzothiazole 249

11.11.2 Nickel-Catalyzed Cross Couplings with Aryl~ and Hetarylmagnesium Halides 250

11.11.2.1 3-Phenylthiophene 251

11.11.2.2 2-{2-Thienyl)furan 251

11.11.2.3 2,2'-Bithienyl 251

11.11.2.4 2-Phenylthiophene 252

11.11.2.5 2,3'-Bithienyl 252

11.11.2.6 2-{ 4-Fluorophenyl)thiophene 252

11.11.2.7 3-{ 4-Fluorophenyl)thiophene 252

11.11.2.8 2-Phenylfuran 252

11.11.2.9 1-Phenylcyclooctene 252

11.11.2.10 1-{ 4-Fluorophenyl)cyclooctene 253

11.11.2.11 4-Methoxybiphenyl 253

11.11.2.12 1-{2-Ethoxyvinyl)-4-fluorobenzene 253

11.11.2.13 2-{2-Ethoxyvinyl)thiophene 253

11.11.2.14 2-{2-Thienyl)pyridine 253

11.11.2.15 3-{2-Thienyl)pyridine 253

11.11.2.16 2,2':5'2"-Terthiophene 254

11.11.2.17 2,3':2'2"-Terthiophene 254

11.11.2.18 2,3':4',2"-Terthiophene 254

11.11.2.19 2-{2-Fluorophenyl)thiophene 254

11.11.2.20 2-{2-Trifluoromethylphenyl)thiophene 254

11.11.2.21 Unsatisfactory Results ; 255

11.11.2.22 2-{3-Thienyl)furan 256

11.11.2.23 2-{3-Thienyl)pyridine 257

11.11.2.24 2-Vinylthiophene 257

11.11.2.25 Z-5-{2-Thienyl)pent-4-en-1-o1 258

11.11.3 Palladium-Catalyzed Cross-Couplings with Grignard Compounds and Organozinc Halides 259

11.11.3.1 2-Vinylfuran 259

11.11.3.2 I-Methyl-2-vinylpyrrole 260

11.11.3.3 4-Fluorostyrene 261

11.11.3.4 2-(2-Furyl)pyridine 262

11.11.3.5 3-(2-Furyl)pyridine 262

11.11.3.6 3-Phenylpyridine 262

11.11.3.7 4,4'-Difluorobiphenyl 263

11.11.3.8 2,4' -Difluorobiphenyl 263

11.11.3.9 4-Fluorobiphenyl 263

11.11.3.10 2(3-Fluorophenyl)furan 263

11.11.3.11 2-(1-Methyl-2-pyrrolyl)pyridine 264

11.11.3.12 I-Methyl-2-(2-thienyl)pyrrole 264

11.11.3.13 2-(4-Fluorophenyl)-I-methylpyrrole 265

11.11.3.14 2-(2-Furyl)-I-methylpyrrole 265

11.11.3.15 2,2':5',2"-Terfuran 265

11.11.3.16 Thiophene-2,5-diyl-2,2'-difuran 266

11.11.3.17 Thiophene-2,5-diyl-2,2'-difuran 266

11.11.3.18 3-Bromo-2-(2-thienyl)thiophene (Selective Substitution of the 2-Bromine Atom in 2,3-Di-bromothiophene) 267

11.11.3.19 2-Bromo-5-(2-thienyl)thiophene 267

11.11.4 Palladium-Catalyzed Reaction of Arylmagnesium Bromides with Trichloroethene 268

11.11.4.1 1,2-Dichlorovinylbenzene 268

11.11.4.2 2-(1,2-Dichlorovinyl)thiophene 268

11.11.4.3 2-(1,2-Dichlorovinyl)furan 268

11.11.4.4 1-(1,2-Dichlorovinyl)-4-fluorobenzene 268

11.11.5 Palladium-Catalyzed Couplings with Alkynylzinc Halides 269

11.11.5.1 2-(1,3-Pentadiynyl)thiophene 269

11.11.5.2 2-(1-Butynyl)thiophene 269

11.11.5.3 Dec-l-en-4-yn-3-one 270

11.11.5.4 I-Phenylbut-2-yn-l-one 271

11.11.6 Palladium-Catalyzed Reaction of Aryl- and Hetarylzinc Halides with Ethyl Chloroformate 271

11.11.6.1 Ethyl-l-methylpyrrole-2-carboxylate (1-Methyl-pyrrole-2-carboxylic Acid Ethyl Ester) 271

11.11.7 Palladium-Catalyzed-Cross Couplings with Boronic Acids 272

11.11.7.1 3-(2-Thienyl)pyridine 272

11.11.7.2 2-(3-Nitrophenyl)thiophene 272

11.11.7.3 3-(2-Thienyl)benzaldehyde 273

11.11.7.4 Other Cross Couplings with Boronic Acids 273

11.11.8 Palladium-Catalyzed Cross-Couplings with Tin Derivatives 274

11.11.8.1 3-(4-Methylthiazol-2-yl)pyridine 274

11.11.8.2 2-( 4-Methylthiazol-2-yl)thiophene 274

11.11.8.3 3-(2-Furyl)benzaldehyde 274

11.11.8.4 Other Coupling Reactions with Organotin Derivatives 275

Table of Contents XIX

Index of Reaction Types 313

Index of Experimental Procedures 315

Complementary Subject Index 327

1 Catalysts, Ligands and Reagents

Although several transition metal catalysts are commercially available, one may fer to make them oneself iflarger quantities are needed The procedures described in this chapter are taken from the literature, but in some of them modifications have been introduced in order to facilitate their performance

pre-1.1 Catalysts

1.1.1 Copper Halides

Copper(I) chloride and the corresponding bromide and iodide (CuX or CU2XZ) are almost colourless compounds Molecular weights for CuX are 98.9, 143.4 and 190.4, respectively Due to oxidation a light-green or - in the case of CuI - light-brown colour appears during storage, but the small traces of Cu(II) present in most cases do not affect the intended result of a reaction in which the salts are used in catalytic amounts The preparations of CuBr and CuCI are described in Vogel's Textbook of Practical Organic Chemistry, 5th ed., Longman, London (1991) p 428 and by C.S Mar-vel and S.M Mc Elvain in Org Synth., ColI Vol 1 (1941), 170, respectively

For some reactions the use of the complex Cu(I)Br·(CH3)2S (molecular weight 205.5)

is recommended (e.g by H.O House, c.-Y Chu, J.M Wilkins and M.J Umen, J Org Chern (1975) 40,1460) Catalytic reactions are sometimes carried out in the presence

of additional amounts of dimethyl sulfide, which serve to increase the solubility of the intermediary complex A serious disadvantage is the stench of the sulfide liberated during the work-up

1.1.1.1 Solubilization of Copper{l) Halides

Copper(I) halides can be solubilized by shaking the powders with a solution of an excess of anhydrous lithium bromide in tetrahydrofuran In this way (concentrated) solutions of the cuprate LiCuXBr can be prepared These may have a rather dark green

or brown colour, caused by the presence of small amounts of Cu(II) The advantage of using these solubilized copper(I)halides over addition of the powders in a catalytic reaction with an organometallic reagent is that the catalyst is quickly and homoge-neously distributed

2 1 Catalysts, Ligands and Reagents

1.1.2 Nickel Catalysts

1.1.2.1 Nickel(ll)bromide·bis(triphenylphosphane)

NiBrz(Ph3Ph, mol weight 742.8, air-stable, green powder

Preparation: (Cf K Yamamoto, Bull Chern Soc Japan (1954) 27, 501.) At 70°C, 60.0

g (0.23 mol) of triphenylphosphane was dissolved in 350 ml of 96% ethanol A

solu-tion of 27.3 g (0.10 mol) of NiBrz"3HzO in 100 ml of ethanol (70°C) was added over a

few min with efficient mechanical stirring After stirring for 1 h at 60-65 °C, the thick suspension was allowed to cool to room temperature The precipitate was filtered off

on a sintered-glass funnel (G-3), washed three times with 75 ml-portions of ethanol and subsequently dried in vacuo (rotary evaporator-water aspirator, then oil pump,

<1 mmHg pressure) The yield was 50 g

1.1.2.2 Nickel(ll)chloride·bis(triphenylphosphane)

NiClz(Ph3Ph, mol weight 653.9, dark-green powder, can be prepared in an analogous way

1.1.2.3 Nickel(lI)chloride.1,3-bis(diphenylphosphino)propane

NiClz"PhzP(CHzhPPhz (NiClz"dppp), mol weight 541.8, red, air-stable powder

Preparation: (Cf G.R Van Hecke, W DeW Horrocks, Jr., Inorg Chern (1960) 5, 1968.) Nickel(I1)chloride"6HzO (4.8 g, 0.02 mol) was dissolved in 100 ml of methanol A warm (-60°C) solution of 8.2 g (0.02 mol) of 1,3-bis(diphenylphospino)propane (see Sect 1.2.1.2) in 70 ml of tetrahydrofuran was added over 1 min with efficient stirring After an additional half hour (at -60°C) the suspension was cooled to room tempera-ture and then filtered on a sintered-glass funnel (G-3) The solid was washed twice with 30-ml portions of methanol and subsequently three times with 30-ml portions of water The red powder was dried in vacuo (rotary evaporator, then oil-pump vacuum

of <1 mmHg) Yield 10.1 g (86.4%)

1.1.2.4 Nickel(ll)chloride.1,2-bis(diphenylphosphino)ethane

powder was prepared in a similar way from NiClz"6HzO and PhzPCHzCHzPPhz (see

Sect 1.2.1.1)

1.1.2.5 Nickel(ll)chloride·1,4-bis(diphenylphosphino)butane

NiClz·PhzP(CHz)4PPhz (NiClz"dppb), mol weight 555.8 (purple powder), was

ob-tained in a similar way from NiClz"6HzO and PhzP(CHz)4PPhz (see Sect 1.2.1.3) in almost quantitative yield

1.1.2.6 Nickel(ll)chloride·1, 1 '-bis(diphenylphosphino)ferrocene

(NiCI2·dppf), mol weight 683.8, dark green, air-stable powder

Preparation: Dppf (1,1' -bis( diphenylphosphino )ferrocene) (Sect 1.2.2), (5.54 g, 0.01 mol) was dissolved in 35 ml of toluene heated at -65 DC A s.olution of 0.0 1 mol (2.4 g)

of NiCI2·6H20 in 15 ml of ethanol was added to the stirred warm solution After ring for 1 hat -60 DC, the suspension was cooled to -10 DC and fIltered on a sintered-glass funnel (G-3) The solid was successively washed with cold (0 DC) ethanol and pentane The solid was dried in vacuo (rotary evaporator, then oil-pump vacuum <1 mmHg) The yield was 5.4 g (79%)

stir-1.1.2.7 Nickel(ll)bromide·1,1'-bis(diphenylphosphino)ferrocene

(NiBr2·dppf), mol weight 772.7, black, air-stable powder, was prepared in a similar way from dppf and NiBr2·3H20 The yield was -90%

1.1.2.8 trans-Chloro(1-naphthyl)bis(triphenylphosphane)nickel

ClOH7NiCI(PPh3b mol weight 745.2, yellow, air-stable powder

Preparation: (Cf J van Soolingen, H D Verkruijsse, M.A Keegstra, L Brandsma, Synth Commun (1990) 20, 3153.) A stirred mixture of 48.0 g (0.20 mol) of NiCI2·6H20, 115.3 g (0.44 mol) of triphenylphosphane and 900 ml of 96% ethanol was heated until a gentle reflux started 1-Chloronaphthalene (0.4 mol, 65 g, excess) was then added, followed by zinc dust (13 g, -0.2 mol, Merck, analytical grade) over 5 min The dark-green mixture very soon turned yellow After stirring and heating under reflux for 1.5 h (under nitrogen), the mixture was cooled to 20 DC Four 20-ml portions of 30% aqueous hydrochloric acid were added over 15 min After stirring for -1.5 h, the solid was filtered off on a sintered-glass funnel and successively washed with 200 ml of ethanol, twice with 200 ml of 1M aqueous hydrochloric acid, twice with

200 ml of 96% ethanol and once with 200 ml of pentane The yellowish solid was dried

in vacuo (first rotary evaporator, then oil-pump vacuum < 1 mmHg, bath temperature not higher than 45 DC) The yield was at least 80%

4 1 Catalysts, Ligands and Reagents

1.1.2.9 trans-Bromo(1-naphthyl)bis(triphenylphosphane)nickel

and trans-Bromo(phenyl)bis(triphenylphosphane)nickel

weight 790.0, orange, air-stable powder, and phane)nickel, C6HsNiBr-(PPh3b mol weight 740.0, orange, air-stable powder, can be prepared by a procedure, similar to 1.1.2.8, from PPh3, the corresponding aryl bro-mides and NiBr2·3H20

trans-bromophenyl)bis(triphenylphos-1.1.3 Palladium Catalysts

1.1.3.1 Palladium(ll)chloride.bis(acetonitrile)

PdCI2(CH3CNh, mol weight 259.3, yellow, air-stable powder

dry acetonitrile was stirred magnetically and heated under reflux until the PdCl2 had dissolved completely (-2-3 h), then the hot solution was concentrated in vacuo The last traces of acetonitrile were removed at a pressure of <1 mmHg

1.1.3.2 Palladium(ll)chloride·bis(benzonitrile)

PdCI2(PhCNh, mol weight 383.5, can be prepared by a similar procedure (cf M.S Kharash, R.C Seyler, F.R Mayo, J Am Chern Soc (1938) 60, 882)

1.1.3.3 Palladium(ll)chloride·bis(triphenylphosphane)

PdCI2(PPh3h, mol weight 701.6, light-yellow, air-stable powder

chloride and 4 g of anhydrous lithium chloride in 150 ml of methanol was heated at 60°C until the red-brown solid had dissolved (-15 min) A solution of 13.1 g (0.05 mol, excess) of triphenylphosphane in 25 ml of warm (50°C) tetrahydrofuran was added in one portion The mixture was stirred at -50°C until the brown colour had disappeared completely (1 to 2 h) The yellow suspension was cooled to room temperature and then filtered on sintered glass (G-3 filter) The solid was successively washed twice with 30-

ml portions of methanol and once with dry ether After drying in vacuo (rotary rator, then oil-pump vacuum), the product was obtained in 90-95% yield

evapo-For another procedure, which uses DMF as a solvent, see A.O King, E Negishi, J

Org Chern (1978) 43, 358

1.1.3.4 Paliadium(lI)chloride·1,4-bis(diphenylphosphino)butane

PdCI2·Ph2P(CH2)4PPhz, (PdCI2·dppb), mol weight 603.5, light-yellow, air-stable der

pow-Preparation: (Cf D.R Coulson, Inorg Synth (1972) 13,121.) A stirred mixture of 0.02 mol (3.54 g) of finely powdered palladium(II) chloride, 4 g of anhydrous lithium chlo-ride and 300 ml of methanol was heated at 60°C until a clear solution had formed A warm solution of 0.02 mol (8.5 g) of 1,4-diphenylphosphinobutane (dppb) (see Sect 1.2.1.3) in 60 ml of tetrahydrofuran was added over a few seconds After 45 min (at -50°C) the light-yellow suspension was cooled to 20°C and filtered on sintered glass (G-3 filter) After washing twice with 30-ml portions of methanol (20°C) and twice with ether, the solvent was removed in vacuo (rotary evaporator, then oil-pump vacu-

um, < 1 mmHg) to give the complex in greater than 90% yields

1.1.3.5 Palladium(ll)chloride·1, l' -bis(diphenylphosphino)ferrocene

PdCI2·dppf, mol weight 731.5, air-stable orange-red powder

Preparation: (Cf T Hayashi, M Konishi, M Kumada, Tetrahedron Lett (1979) 1871.) 1,I-Bis(diphenylphosphino )ferrocene (0.02 mol, ILl g) (see Sect 1.2.2) was dissolved

at 65°C in 75 ml of toluene To the stirred solution was added a solution of 3.54 g (0.02 mol) of palladium(II)chloride and 3 g of anhydrous lithium chloride in 100 ml of 96% ethanol (for complete dissolution of PdCl2 heating for -1 h at 70°C was required) After an additional 30 to 45 min (at 70°C) the suspension was cooled to 20 °C and fil-tered on sintered glass (G-3 filter) The solid was washed three times with 25-ml por-tions of ethanol and subsequently twice with dry ether After drying in vacuo (bath temperature -40°C) PdCl2·dppfwas obtained in almost quantitative yield

1.1.3.6 Tetrakis(triphenylphosphane)palladium(O)

Pd(PPh3)4' mol weight 1155, yellow, microcrystalline powder It should be stored under inert gas, since it slowly turns brown upon exposure to air (without seriously affecting the catalytic activity, however)

Preparation: (Cf D.R Coulson, Inorg Synthesis (1972) 13, 121.) In a 500-ml necked round-bottomed flask 3.54 g (0.02 mol) of finely powdered PdCl2 and 26.2 g (0.10 mol) of triphenylphosphane were dissolved in 240 ml of dimethylsulfoxide with heating and magnetic stirring (we found cautious heating with an open flame more practical than with an oil bath) When at -140°C all PdCl2 had dissolved, heating was stopped and hydrazine hydrate (NH2NH2-H20) (4.1 g) was added over -1 min by syringe The colour became darker, while nitrogen was evolved One minute after this addition the mixture was cooled (water-bath) until the solution became turbid The still hot suspension was stirred (without cooling bath) for an additional 20 min and subsequently cooled to 20°C The solid was filtered off on sintered glass (G-3), washed three times with 35-ml portions of ethanol and subsequently twice with 40-ml portions of diethyl ether After drying in vacuo (rotary evaporator, then oil-pump vacuum <1 mmHg, bath temperature -45°C), 22 g (-95% yield) of yellow powder remained

one-6 1 Catalysts, Ligands and Reagents

1.1.3 7 Tris{dibenzylideneacetone}dipalladium{O}·chloroform

Pdz(dbah·CHC13, mol weight 1035, purple crystals (dba = PhCH=CH-CO-CH= CHPh)

Chern {1974} 65, 253.) Palladium(II} chloride (1.05 g, 5.92 mmol) was added to a solution of 4.60 g {19.6 mmol) of dibenzylideneacetone and 3.90 g (47.5 mmol) of sodium acetate in 150 ml of methanol, heated at 50 DC After stirring for 4 h at 40 DC,

the mixture was allowed to cool The purple precipitate was filtered off on sintered glass and successively washed with water and acetone After drying in vacuo, the sol-

id (3.39 g) was dissolved in 120 ml of chloroform (60 DC) The violet solution was tered and the filtrate diluted with 170 ml of ether After cooling to 10-15 DC, the purple precipitate was filtered on sintered glass, washed with ether and dried in vacuo The yield was -80%

fil-1.2 Ligands

A variety of phosphorus-containing mono- and bidentate ligands have been (and may be) used to tune the reactivity of transition-metal catalysts Some can be prepared rather easily by one-pot procedures using relatively cheap reagents The synthesis of potentially interesting ligands, such as RzP(CHz}nPRz (with R = prim-, sec-, and tert-

alkyl) and 1,1' -bis( diisopropylphosphino }ferrocene, is experimentally very ing, since it involves the preparation of extremely air-sensitive secondary phosphanes

1.2.1.1 1,2-Bis(diphenylphosphino}ethane

(dppe), mol weight 398.2, air-stable solid

Preparation: (Cf T Yoshida, M Iwamoto, S Yuguchi, JP 11,934 (1967); C A (1968)

68, 105358 e; W Hewertson, H.R Watson, J Chern Soc (1962) 1490.) In a 3-1 bottomed, three-necked flask, equipped with an efficient mechanical stirrer and two outlets, was placed 1.5 L of anhydrous liquid ammonia (see Note 1) A solution (-35°C) of 52 g (0.20 mol) of triphenylphosphane in 75 ml of tetrahydrofuran was cautiously poured into the flask (with both outlets temporarily being removed) Sodium (see Note 2) was cut in pieces of -0.5 g each and these were introduced into the efficiently stirred mixture over 45 min Usually, somewhat more than the theoret-ically required amount of 0.40 mol (9.2 g) was needed to cause a persisting (for at least 15 min) very dark colour of the solution (between brown and blue, the colours

round-of dissolved Ph2PNa and Na, respectively) Fifteen min aft~r this addition a powder funnel was placed on one of the necks and finely powdered ammonium chloride (8 g) was introduced in 0.5 g-portions over 15 min with vigorous stirring (to neutralize most of the sodamide formed in the cleavage reaction) The powder funnel was then replaced with a dropping funnel containing a mixture of 0.10 mol (-lOg) of 1,2-dichloroethane (see Note 3) and 20 ml of diethyl ether This mixture was added drop-wise over 45 min to the vigorously stirred suspension (if 10 min after completion of this addition the mixture is still brown, an additional small amount of dichloroethane has to be added dropwise until the brown colour disappears) The ammonia was allowed to evaporate overnight After addition of 500 ml of water, the product was extracted with small portions of chloroform The organic solution was dried over magnesium sulfate and subsequently the solvent was completely removed

by evacuation (rotary evaporator, then oil-pump vacuum <1 mmHg) The white

sol-id was purified by crystallization from a 1 : 5 mixture of tetrahydrofuran and diethyl ether The yield was -70%

IH NMR spectrum (CDC13): 7.1-7.4 (m, 20H); 2.15; (t, 4H) ppm

Notes:

1 Small amounts of water «0.1 to 0.2%) do not seriously affect the result, since these are "neutralized" by the alkali amide formed in the cleavage The greater part (but not all) of the water in the ammonia can be neutralized by adding small (0.1 to 0.2 g) pieces of sodium or potassium (at intervals of 1 to 2 min) until the blue colour persists longer than 10 min

2 Lithium may also be used

3 Dibromoethane cannot be used, since Ph2PPPh2 is formed by attack ofPh2P- on Br and subsequent fast reaction of Ph2P- with Ph2PBr produced in the first step

1.2.1.2 1,3-Bis(diphenylphosphino}propane

(dppp), mol weight 412.2, air-stable solid, was prepared in an excellent yield as described in Sect 1.2.1.1 Instead of 1,3-dichloropropane the dibromide may be used

IH NMR spectrum (CDC13): 7.1-7.4 (m, 20 H); 2.1-2.3 (m, 4H); 1.3-1.8 (m, 2 H) ppm

8 1 Catalysts, Ligands and Reagents

(dppf), mol weight 554.2, orange, air-stable crystals

J.e Smart, J Organometal Chern (1971) 27, 241; J.D Unruh, J.R Christenson, J Mol Catal (1982) 14,19.) A l-l-three-necked, round-bottomed flask was equipped with a magnetic stirrer, a thermometer-gas inlet combination, and a reflux condenser The flask was purged with nitrogen and charged with 9.2 g (50 mmol) of ferrocene and

250 ml of hexane A solution of 1.6 M n-butyllithium in hexane (67 ml, 107 mmol) was quickly added and the resulting red suspension was stirred at room temperature while 12.0 g (103 mmol) of tetramethylethylenediamine (TMEDA) was added in one portion The temperature rose to 30-35 °C within 5 min The reaction mixture was heated on a water bath at 60°C for one hour, during which the red suspension turned orange The water bath was removed and 100 ml of dry THF (distilled from LiAIH4/benzophenone) was added The orange suspension was cooled to -40°C After removing the cooling bath, a mixture of 24.0 g (109 mmol) of chlorodiphenyl-phosphane and 50 ml of THF was added in three portions over five minutes The temperature of the reaction mixture rose to about -25°C and a yellow suspension was formed The reaction mixture was stirred for an additional 15 min at room tem-

perature Subsequently it was concentrated to ca 20% of its original volume using a

rotatory evaporator, and then filtered on a G-3 glass filter The precipitate was cessively washed with 50 ml of 2 M hydrochloric acid, 50 ml of water, 50 ml of ethanol and 50 ml of ether The resulting fine yellow powder was dried in vacuo to afford 20-22 g, corresponding to 75-80% yield of the desired product The compound was pure according to NMR

suc-lH-NMR spectrum: (300 MHz, CDCI3): 7.3 (m, 20H), 4.3 (s, 4H), 4.0 (s, 4H) ppm;

!3C-NMR spectrum (75MHz, CDCI3): 138.7 (d, 4C), 133.3 (d, 8C), 128.2 (d, 8C), 128.1 (s, 4C), 76.5 (d, 2C), 73.6 (d, 4C), 72.4 (d, 4C) ppm; 3 1p-NMR spectrum (121 MHz, CDCl3, 85% H3P04 as external standard): -16.6 (s) ppm

1.2.3 Triarylphosphanes and Tri(hetaryl)phosphanes

butyllithium - are amply illustrated with experimental procedures in L Brandsma, H.D Verkruijsse, Preparative Polar Organometallic Chemistry, Vol 1, Springer-Ver-lag, Heidelberg (1987) Therefore it will be sufficient if we describe a general proce-dure for the reaction of phosphor trichloride with aryl- or h~taryllithium compounds

Preparation: In a 1-1 round-bottomed flask, equipped with a thermometer-gas inlet combination, a mechanical stirrer and an outlet, is prepared (under inert gas) 0.105 mol of the organolithium intermediate (see Note 1) in 100 ml of tetrahydrofu-ran and 68 ml of hexane After cooling to between -80 and -90°C (bath with liquid nitrogen, occasional cooling), a mixture of 4.1 g (0.03 mol) of freshly distilled phos-phor trichloride and 20 ml of diethyl ether is added dropwise over 15 min, while maintaining the low temperature After the addition the cooling bath is removed and the temperature is allowed to rise to above 10 dc Water (100 ml) is then added with vigorous stirring (see Note 2) The organic layer is dried over magnesium sulfate and subsequently concentrated in vacuo to give the product It may be crystallized from a suitable solvent or mixture of solvents

2 Some triarylphosphanes are moderately soluble in the THF-hexane mixture and the aqueous work-up may be troublesome because part of the product precipitates

In such cases the THF and hexane should be first removed in vacuo on the rotary evaporator After addition of water to the residue, the product can be extracted with chloroform or dichloromethane

10 1 Catalysts, Ligands and Reagents

1.3 Organometallic Reagents

Organomagnesium and -zinc halides are frequently used intermediates in transistion metal-catalyzed cross-couplings and substitutions In a number of cases, Grignard derivatives are directly accessible by reaction of magnesium with an organic halide A more generally applicable method for obtaining organomagnesium halides is the reaction of an organolithium compound with magnesium halide Organozinc halides are usually prepared by an analogous metal exchange reaction

The use of organoaluminium, -boron and -tin intermediates prm'ides additional possibilities for realizing cross-couplings

1.3.1 Preparation of Grignard Reagents

from Mg and Organic Halides

Problems with the preparation of frequently used Grignard reagents, such as CzHsMgBr and PhMgBr, are mostly effectively solved by following the usual advice (addition of a crystal of iodine or using perfectly dry ether or tetrahydrofuran, com-pare Vogel's Textbook of Practical Organic Chemistry, 5th ed., Longman, London (1991) p 531) The difficulties faced with during preparations of Grignard solutions

from chlorides may be more serious In this section we describe as extensively as

pos-sible the preparation of these Grignard reagents, the problems that may occur, and give some hints to prevent or solve them For extensive practical information about the preparation of several special Grignard compounds the manual of B.J Wakefield [Organomagnesium Methods in Organic Synthesis, Academic Press, London (1995)] should be consulted

The usual protocol for the preparation of Grignard reagents consists of covering magnesium turnings (preferably an excess of at least 20 mol% with respect to the organic halide) with a relatively small amount of diethyl ether or tetrahydrofuran (-150 ml for each mol of Mg) in a flask filled with inert gas Part (e.g 10%) of the halide is then added in one portion (in preparations on a small scale, <0.10 molar, the

reaction is marked by a distinct rise of the temperature (by at least 15°C) in the

sol-vent or from a beginning reflux (in the case of diethyl ether), and from the appearance

of a turbidity Sometimes, the reaction stops and heat is no longer evolved This may

be due to inactivation of the magnesium by a covering layer of alkoxide (presence of ROH in the halide RX) or hydroxide (un carefully dried solvents) The white turbidity may change into a more coarse white suspension In these cases it makes little sense to continue the experiment If the initial reaction has started smoothly, however, the addition of the halide is continued (after the starting reaction has subsided) The desired amount of solvent (not less than 500 ml per mol of halide) is added dropwise

in admixture with the halide The turbidity gradually disappears and a dark-grey solution is formed Generally, the temperature in the flask is kept (by heating or cool-ing) at a moderate level (gentle reflux in the case of ether, between 35 and 55°C in

THF) If too strong cooling is applied during preparations ofRMgX in THF, salty pensions may be formed and the reaction may stop completely As a rule, the prepa-rations are completed by additional heating during 30 to 60 minutes Large volumes

sus-of Grignard solutions, intended to be used for a number sus-of syntheses, can be

decant-ed from the excess of magnesium in a calibratdecant-ed flask (filldecant-ed with inert gas) using the Schlenck technique Most Grignard reagents are stable at room temperature The

stopper of the storage flask should be regularly greased during storage in order to

prevent it from getting stuck Grignard reagents in THF often partly crystallize out at room temperature: therefore, the flask must be warmed (with manual swirling) at 30-40 °C prior to using part of the solution This rather boring opzration may be avoided in most cases by keeping the concentration below 0.8 mollI Estimation of Grignard solutions may be carried out with butan-2-01 using an indicator, such as 2,2' -bipyridyl or 1,10-phenanthroline (see Vogel's Textbook of Practical Organic Chemistry, 5th ed., Longman, London (l991), p 443) Most of the alkyl- and aryl-magnesium halides can be prepared with "yields" ~etween 85 and 90%, for

H2C=CH-CHzMgBr (see below) and t-BuMgCI -80% and -70%, respectively are attainable

In addition to using perfectly dried solvents (carefully stored under nitrogen), the following measures may be taken to make the chance of a smooth start of a Grignard preparation as high as possible

1 Stirring the alkyl halides with a substantial amount of finely powdered anhydrous calcium chloride (the use of alumina also may be considered) and calcium carbon-ate to remove traces of alcohol, water or hydrogen halide, followed by distillation

2 Mechanically activating the magnesium by slowly stirring (under inert gas) the

metal with a small amount of solvent ( -150 ml for 1 mol of Mg) for at least 2.5 h, so that a greyish-black solution is formed Pieces (0.5 to 1 cm) of glass from a broken Pasteur pipette may be added to assist in the activation

3 Some special Grignard reagents, e.g H2C=CH-CHz-MgBr and HzC=C=CH-MgBr can be successfully prepared in diethyl ether at temperatures in the region of 0 °C (for HzC=C=CH-MgBr see 1 Brandsma, Preparative Acetylenic Chemistry, 2nd ed., Elsevier, Amsterdam (l988) The metal is activated first by stirring it for half an hour at room temperature with a solution of mercury(II)chloride in a small amount of diethyl ether (1 to 2 g HgClz for 1 mol of Mg) Subsequently, a small por-tion (-5%) of the halide is added at 0 to 5 °C to the turbid grey solution This should result in a significant rise of the temperature to at least 10°C in spite of cool-ing in an ice-water bath After the reachon has subsided, the remaining amount of halide is added dropwise together with the desired amount of ether while main-taining the temperature between 0 and 5 0c By using a large excess (at least 20 mol%) of magnesium, activating the metal and adding the halide slowly at low temperatures, Wtirtz-dimerization is effectively suppressed

Using mechanically activated magnesium, benzylmagnesium chloride in diethyl ether can be prepared with limited dimerization at temperatures between 10 and 25°C Some organomagnesium halides, e.g I-naphthylmagnesium bromide, are not very soluble in ether or THE As a consequence, the preparation may be troublesome If

a sufficient amount of benzene is used as a cosolvent, no solid appears and the preparation may be carried out without problems

12 1 Catalysts, Ligands and Reagents

1.3.2 Preparation of Organomagnesium and

mag-by warming and temporarily passing a fast stream of nitrogen (or dry air) through the flask The oily, grey solution is decanted from the excess of metal into another flask and weighed It is assumed to contain 0.50 mol of MgBr2' Since the etherate does not crystallize out during storage at room temperature, the amount needed for some reac-tion can be determined by weighing Regular greasing of the stopper of the storage flask is desired

Lithium-zinc exchange reactions (RLi + ZnClz RZnCI + LiCl) also proceed very smoothly The zinc chloride is added most conveniently as a concentrated solution in tetrahydrofuran to the lithium derivative Water present in the commercial anhydrous salt may be removed azeotropically using toluene as a solvent Most of the toluene can

be removed by decantation, followed by washing of the dried salt with pentane and finally evacuation

Warning: It seems risky to leave strongly activated magnesium residues exposed to air Small amounts may be dissolved in dilute aqueous hydrochloric acid, quantities larger than 10 gram can be destroyed (slowly) by aqueous ammonium chloride in a beaker

1.3.3 Preparation of Organoaluminum Intermediates

(see also Chapter 11)

Representative procedures for the stereospecific addition of diisobutylaluminum hydride and trimethylaluminum to acetylenes can be found in Org Synth (1988) 66,

60 and Org Synth., ColI Vol 7 (1990) 245

1.3.4 Preparation of Organoboron and

Organotin Intermediates (for Refs see Chapter 11)

Stereo-defined adducts can be made from acetylenes and diisoamylborane or chylborane and tributyltin hydride Unfortunately, the possibilities for checking the literature procedures were seriously limited by the high price of the boron and tin reagents

cate-Useful boron and tin intermediates can be prepared by simple procedures from organolithium and -magnesium compounds and trialkylborates or trialkyltin chlo-ride A number of experimental procedures using the relatively cheap trimethyl borate and tributyltin chloride are given below

thermometer-Procedure: Under an atmosphere of nitrogen a solution of 0.1 0 mol of BuLi in -65 ml

of hexane was added over a few sec (by syringe) to a mixture of 11 g (excess) of phene and 70 ml of THF cooled at -10°C During the addition the temperature was allowed to rise (without external cooling) to between 20 and 30°C After an addition-aIlS min (at -25°C) the solution was cooled to -90 0C Trimethyl borate (0.20 mol, 20.6 g, see Note 1) was added in one portion (see Note 2) with vigorous stirring, after which the cooling bath was removed Abov:e -70°C the evolution of heat was dearly visible The temperature was allowed to rise to above 10 0C The reaction mixture became somewhat less viscous A mixture of 30 g of 30% hydrochloric acid and 50 ml

thio-of water was added at 10°C followed by vigorous stirring at -30°C for half an hour After separation of the layers, four extractions with ether were carried out Each organic layer was washed twice with a saturated aqueous solution of ammonium chlo-ride (50-ml portions) and the aqueous layers combined with the original one The combined washings were extracted twice with small portions of ether and the extracts washed once with saturated aqueous ammonium chloride The combined organic solutions (almost colourless) were dried over anhydrous MgS04 and subsequently concentrated in vacuo (in the last stage p < 1 mmHg) The weight of almost white crys-

14 1 Catalysts, Ligands and Reagents

talline material corresponded to a yield of -90% The product was not further fied It was stored in the refrigerator

puri-Notes:

1 Trimethylborate is very volatile and moisture-sensitive

2 The use of this large excess and the rapid addition should prevent formation of and tri-substitution products (2-Th)zB(OCH3) and (2-ThhB

por-Note: Washing with water would lead to partial dissolution

Scale, equipment and notes: same as in preceding experiments

Procedure: Under an atmosphere of nitrogen a solution of 0.10 mol of n-BuLi in -65

ml of hexane was added to 90 ml of THF with cooling below 0 0C After cooling the solution to -90°C, 0.11 mol (19.3 g) of 1-bromo-4-fluorobenzene was added over a few sec, while keeping the temperature between -70 and -85°C After an additional 15 min (at 75°C) the suspension was cooled to -95°C and 0.20 mol (20.6 g) of trimethylborate was added in one portion with vigorous stirring and intensive cool-ing After the addition, the cooling bath was removed and the temperature of the colourless solution allowed to rise to -10°C The acid hydrolysis and work-up were carried out in a way similar to the procedure for 2-thiopheneboronic acid The yield of white crystalline material was 85% The product was used as such for cross-couplings

It should be stored in the refrigerator

lH-NMR spectrum (CCI4): 7.61 (m, lH); 6.40 (m, IH); 6.28 (m, IH) ppm

1.3.4.6 1-Methyl-2-tributylstannylpyrrole

n-BuLi-TMEDA h-e-xa-n-e l Cl

N Li

I

CH 3

16 1 Catalysts, Ligands and Reagents

IH-NMR spectrum (CCI4): 6.4S (m, lH); 6.03 (m, 2H); 3.54 (s, 3H) ppm

1.3.4.7 4-Methyl-2-tributylstannylthiazole

Scale and equipment: same as in preceding experiments

Procedure: Under an atmosphere of N 2 ,4-methylthiazole (0.11 mol, 11 g) was added over a few sec to a solution of 0.11 mol of n-BuLi in -70 ml of hexane and 70 ml of THF, while keeping the temperature between -65 and -SO 0C After stirring the sus-pension for 15 min at 75°C, it was cooled to -90°C and 0.10 mol (32.6 g) tributyltin chloride was added over 1 min with vigorous stirring and cooling between -70 and -90°C The reaction mixture was kept for an additional 15 min at 70°C, then the cooling bath was removed and the temperature was allowed to rise to -50°C Pentane (75 ml) was added (see Note) and the susp~nsion was warmed to 10°C It was then fil-tered through a 1-cm layer of anhydrous K2C03 on a G-3 glass filter The solid was rinsed well with dry ether Concentration of the clear filtrate in vacuo (in the final stage a vacuum of <0.5 mm was applied with heating at 60°C) gave the product in -100% yield

IH-NMR spectrum (CCI4): 6.92 (1H); 2.50 (3H) ppm

Note: Aqueous work-up leads to cleavage of the Sn-C bond with partial or complete recovery of the unsubstituted thiazole

1.3.4.8 Stannylation of Ethyl Vinyl Ether

funnel-Procedure: After perfusing with nitrogen, a solution of 0.12 mol of n-BuLi in -75 ml of hexane was placed in the flask A solution of 0.12 mol (13.4 g) of potassium t-butoxide (the commercially available base was used) in 80 ml of THF was added over 5 min with efficient stirring, while keeping the temperature between -85 and -100°C (occa-sional cooling in a bath with liquid nitrogen) Subsequently, 0.3 mol (21 g, a large excess) of freshly distilled ethyl vinyl ether was added over 5 min The solution was stirred for 10 min at -80°C, after which the temperature was allowed to rise over 15 min to -40 0c Tributyltin chloride (0.10 mol, 32.5 g) was added over 5 min at -60 to -70°C, after which the cooling bath was removed and the temperature allowed to rise

to 0 0c Water (100 ml) was added with vigorous stirring The organic layer was dried over anhydrous MgS04• Concentration in vacuo gave the product in almost 100% yield If desired, the product can be distilled at a low pressure through a very short column

lH-NMR spectrum (CCI4): 4.55 (d, lH); 3.87 (d, lH); 3.60 (q, 2H) ppm

2 Procedures for the

Preparation of Halogen Compounds

Halogen compounds are frequently used and often indispensable substrates for coupling reactions and nucleophilic substitutions In this chapter experimental pro-cedures are given for a number of halides with relatively simple structures that are either not (yet) commercially available, very expensive or have a limited stability The procedures are modifications or optimizations of published ones A number of substi-tuted aryl halides can be prepared by well-established methods Several experimental procedures can be found in B.S Furniss, A.J Hannaford, P.W.G Smith, A.R Tatchell,

cross-"Vogel's Textbook of Practical Organic Chemistry", 5th ed., Longman Scientific & Technical, London (1991)

Apparatus: 1-1 round-bottomed, three-necked flask!, equipped with a nitrogen

inlet-thermometer combination, an efficient, gas-tight mechanical stirrer and a cold finger filled with dry ice and acetone (for the preparation of the hypobromite solution the flask was equipped with a dropping funnel, a mechanical stirrer and a thermometer-outlet combination)

mol, 96 g) was added over -15 min to a vigorously stirred solution of 90 g of

potassi-um hydroxide (technical quality, -15% H20) in 200 ml of water, while keeping the temperature between -5 and 0 DC (bath with dry ice and acetone) The yellow solution

In all preparations described in this book round-bottomed flasks with vertical necks were used

was covered with 40 ml of high-boiling petroleum ether (b.p > 190 °C1760 mmHg) and the flask equipped for the reaction with the alkyne After the air had been replaced completely by nitrogen, the mixture was brought to 0 °C in the case of propy-

ne, or +5 °C in the case ofbutyne A cold (-20°C) solution of 0.40 mol (16.0 and 21.6

g, respectively) of the alkyne in 120 ml of high-boiling petroleum was added in five portions over 15 min with vigorous stirring (the inlet being removed during the addi-tions) The temperature of the mixture gradually rose to between 15 and 20°C A slow stream of nitrogen was passed through the flask After addition of the last portion, the reaction was monitored by determining the refractive index of the supernatant layer (stirring was temporarily stopped) Stirring was continued for an additional halfhour after the nD had become maximal After addition of 200 ml of water, the layers were separated under nitrogen The organic layer was transferred into a 2-1 round-bot-tomed flask (filled with nitrogen) containing boiling stones and 10-15 g of anhydrous magnesium sulfate After vigorous shaking, the flask was equipped for a vacuum dis-tillation: 40-cm Vigreux column, condenser and single receiver cooled at -75°C The system was evacuated (water aspirator) and the temperature of the heating bath grad-ually raised, until the petroleum began to reflux in the upper part of the column Rep-etition of this procedure with the contents of the receiver (raising the bath tempera-ture gradually from 10 to 40°C) gave pure 1-bromo-l-propyne, n20D 1.472, and I-bro-mO-l-butyne, n20D 1.470, in greater than 80% yields

Warnings:

1 I-Halo-l-alkynes, especially I-bromo-l-propyne, are oxygen-sensitive All

opera-tions therefore should be carried out under inert gas Vapours of

I-bromo-1-propy-ne may ignite upon contact with air The compounds should be stored in sealed bottles in the refrigerator

well-2 In view of the suspected physiological effects, all operations should be carried out

in a well-ventilated hood The characteristic smell of I-bromo-l-alkynes is easily

inlet-thermometer combination, an efficient mechanical stirrer and an outlet; see also ceding experiment

pre-ceding experiment (the same amounts were used) After the air in the flask had been replaced by nitrogen, the l-alkyne (0.30 mol, 20.4 and 24.6 g, respectively) was added

rela-n20D 1.468, and 1-bromo-1-hexyne, b.p 35 °C112 mmHg, n20D 1.466, in excellent yields

2.1.3 Other 1-Bromo-1-alkynes

The bromination of 1-heptyne and higher homologues with potassium hypobromite expo 1.1 proceeds much more slowly, because of their decreased solubility in the aque-ous phase The following method is recommended:

n-BuLi RC",CH • RC",CLi • RC",C-Br

EtzO-hexane low temp

Instead of n-butyllithium an ethereal solution of ethylmagnesium bromide may be used for the metallation of the alkyne

The kinetically and thermodynamically more acidic enynes RCH=CH-C=CH, diynes RC=C-C=CH and aryl- or hetarylacetylenes can be easily brominated by the KOBr-method Also for acetylenic alcohols, e.g HC=C-C(CH3hOH, this method is applicable In the case of primary or secondary acetylenic alcohols, e.g HC=C-CH(CH3)OH, inversed addition must be applied in order to avoid subsequent reac-tions

For the various procedures L Brandsma, Preparative Acetylenic Chemistry, 2nd ed., Elsevier, Amsterdam (1988) should be consulted

sys-tem, e.g Ar-C=C-Br and RC=C-C=C-Br have a decreased thermal stability tive purification of bromides with a conjugated diyne system should not be carried out

Distilla-2.1.4 Reaction of Alkynyllithium with Iodine in

Organic Solvents

[See L Brandsma, Preparative Acetylenic Chemistry, 2nd ed., Elsevier, Amsterdam (1988) p 152.]

THF or Et?O-hexane RC",CLi + 12 - ~ RC",CI + Lil

<-20°C

powder) funnel-nitrogen inlet combination, a mechanical stirrer and a outlet combination

powder funnel) or a saturated solution of 0.20 mol of iodine in Et20 or THF was added over 15 to 30 min to a solution or suspension of 0.20 mol of the lithiated acety-lene (see literature mentioned above) in a mixture of Et20 and hexane or THF and hexane with cooling between -15 and -30°C After this addition, the cooling bath was

removed and the temperature was allowed to rise to about 0 °C (suspensions of

RC=CLi may react more slowly) Water (200 ml) was then added with vigorous ring, and, after separation of the layers, the aqueous layer was extracted with Et20 (small amounts OfI2 can be removed with an aqueous Na2S203 solution) The organic solutions were dried over MgS04 and subsequently concentrated in vacuo, followed

stir-by distillation of the remaining liquid C4HgC=CI, b.p 60 °CflO mmHg, n200 1.5166,

was obtained in >80% yield Volatile iodoacetylenes (b.p <40 °C/10 mmHg) can best

be prepared by using Et20 as the only solvent The lithium alkynylide is generated from the acetylene and EtLi.LiBr in Et20 For another useful procedure for volatile iodoacetylenes see the expo in Sect 2.1.5 Acetylenic Grignard derivatives in Et20 or THF also give iodoalkynes upon addition of iodine at -10 to -20°C

2.1.5 Preparation of lodoacetylenes from lithiated Acetylenes and Iodine in liquid Ammonia

liq NH3 RC",CLi + 12 -.~ RC",CI + LiI

< -40 °c

NI3 as a black precipitate In anhydrous liquid ammonia at -33°C (or at lower

tem-2.1 sp-Halides 23

peratures), however, practically no conversion takes place This appears most vincingly from the fact that aryl- or heteroaryl iodoacetylenes can be prepared in excellent yield by stirring a mixture of equimolar amounts of iodine and the acetylene

con-in liquid ammonia for several hours For the less acidic alkylacetylenes, this method

has no practical importance, since very long reaction times are needed A much quicker procedure is to add iodine as a solution in Et20 or THF to an ammoniacal solution of the lithiated acetylene, cooled to below -33°C: this reaction is almost instantaneous and generally gives iodoacetylenes in excellent yields The volatile iodopropyne, for example, can be prepared by adding an ethereal solution of iodine to

a solution of propynyllithium in ammonia cooled to below -60°C Under these tions the iodination proceeds almost instantaneously

condi-The alternative method for volatile iodoacetylenes - RC=CLi + 12 in Et20 - is more time consuming, since it requires preparation of a solution of EtLi.LiBr from ethyl bromide and lithium in Et20

ammo-nia was prepared by addition of a 10% molar excess of the alkyne to a suspension of

0.20 mol ofLiNH2 Propynyflithium and butynynithium can best be prepared by

drop-wise addition (over 20 min) of the l,2-dibromoalkanes (0.20 mol) to a suspension of a slight excess of LiNH2 (0.70 mol) in -600 ml of liquid ammonia The solutions in ammonia were cooled to below -60°C (occasional cooling in a bath with liquid N2), while N2 was passed through the flask (0.5 Umin) A solution of 0.25 mol (excess) of iodine in Et20 (-300 ml) or THF (250 ml) was then added over -15 min with efficient stirring, while keeping the temperature between -50 and -70°C (for the volatile iodoalkynes with b.p <50 °C115 mmHg, Et20 should be used) After an additional 15 min (at 50°C) the reaction mixture was cautiously poured onto 500 g of finely crushed ice, contained in a 2 to 3-1 wide-necked conical flask The reaction flask was rinsed with a small amount of ice water A solution of 20 g of Na2S203 in 150 ml of water was then added to the mixture After melting of the ice (some warming might

be applied) and vigorous shaking, the layers were separated The aqueous layer was extracted three to five times with small portions of pentane (this gives a better sepa-ration than Et20) The combined organic solvents were dried over MgS04' after which the greater part of the solvent was removed: in the cases of CH3C=C1, C2HsC=C1 and C3H7C=C1, the Et20 was distilled off at atmospheric pressure through

a 40-cm Vigreux column under reduced pressure CH3C=C1, b.p -50 °C/100 mmHg, n20D 1.5500, and CSHIIC=C1, b.p 78 °C/l0 mmHg, n20D 1.5105, were obtained in excellent yields